Our goal is to identify major genetic risk factors for the development of systemic lupus erythematosus (SLE) that are common to multiple ethnic groups. During the last decade, more than 10 whole genome linkage scans have mapped many SLE susceptibility loci. Evidence for linkage to SLE at 1q23-25 and 1q31-32 have been identified and confirmed by our group and other investigators using multiplex families of Caucasian, African- American, Mexican-American, or other ethnic origins. We hypothesize that 1q contains SLE susceptibility genes shared by more than one ethnic group. To this end, we have evidence for association of SLE susceptibility with four positional candidate genes (PBX1 and OX40L in 1q23-25, and CFH/CFHR3/CFHR1 and CR2 in 1q31-32) in two or more ethnic groups, including association of copy number variants (CNVs) of CFH/CFHR3/CFHR1 with SLE. An anonymous 1q25.1 locus has recently been identified as one of the 4 novel associations with SLE in whole genome association (WGA) and replication studies of Caucasian cases and controls conducted by the SLE Genetic consortium (SLEGEN) using 317,000 SNPs. Because of the high cost of WGA for replicating in independent Caucasian samples and for extending WGA to each of the non- Caucasian ethnic groups, we propose to conduct a targeted genome association study using both high-density SNPs and CNVs covering the two 1q intervals (1q23-25 plus 1q31-32) that have strong linkage and association evidence in multiple ethnic groups. In addition, we plan to assess novel genes identified in WGA studies in SLE and other autoimmune diseases for association with SLE in our independent samples. Samples available for this study are from > 15,000 subjects including Caucasian, Asian, and African-American cohorts. We anticipate that these experiments will identify major genetic effects located in chromosome 1q as well as novel gene variants associated with SLE that are common to several ethnic groups. Results of these association studies will lead to localization of causal gene variants (SNPs and/or CNVs), and characterization of their effects on the gene products. Knowledge gained from these studies may reveal new paradigms for the pathogenesis of the disease, and may provide new therapeutic targets for disease management. Common risk variants to several, but not all, autoimmune diseases will help elucidate both shared and unique pathways underlying these complex disorders. 7. PUBLIC HEALTH RELEVANCE This study aims to identify major genetic risk factors, located on the long arm of chromosome 1, that increase risk for systemic lupus erythematosus (SLE). If we identify a particular genetic factor that is shared by more than one ethnic group, it is likely to play an important role in the pathogenesis of lupus. The identification of novel genes common to multiple ethnic groups will yield new insights into the mechanisms underlying the disease, which may lead to the development of specific targets for therapeutic interventions.